Melanocytes, i.e., pigment-producing cells in the skin, eye, and mucosal surfaces, give rise to a spectrum of proliferative lesions ranging from benign nevi to overtly malignant melanoma. Melanoma is a disease with high metastatic potential even at very early stages of development. Melanoma accounts for less than 5% of skin cancer cases, but causes a large majority of skin cancer deaths (Cancer Facts & Figures, American Cancer Society, Atlanta, Ga. (2010)). Melanoma is notorious for its resistance to chemotherapy and radiotherapy (Sondak, Cancer J., 7 (Suppl. 1): S24-27 (2001)), so early, accurate diagnosis of melanocytic proliferations remains the key to reducing morbidity and mortality.
Unfortunately, melanocytic lesions exhibit striking heterogeneity in terms of morphology and biologic behavior, which can make their diagnosis challenging for even the most experienced dermatopathologists. Lesions that are neither clearly benign nor clearly malignant have been historically grouped as “melanocytic tumors of uncertain malignant potential (“MELTUMP”). Progress has been made in developing objective histologic criteria for the diagnosis of these indeterminate lesions (Magro et al., J. Am. Acad. Dermatol., 62(3): 469-479 (2010)), but inconclusive diagnoses may still affect the clinical management of patients, who may be subjected to unnecessarily aggressive surgery, adjuvant treatments, chemotherapy, immunotherapy, or radiation therapy.
Although histologic examination of tissue biopsies remains the gold standard in the diagnosis of melanocytic proliferations (Soyer et al., Color Atlas of Melanocytic Lesions of the Skin, p. 23 (Springer-Verlag, Berlin, 2007)), the clinical value of adjunct diagnostic techniques is becoming increasingly realized. Information about the genetic make-up and/or protein expression patterns of a lesion can be used to confirm or disaffirm a diagnosis reached through histologic examination.
Examples of adjunct diagnostic techniques include comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and immunostains. CGH and FISH make use of DNA probes to provide information about genetic aberrations in a tissue sample (Blokx et al., Histopathol., 56: 121-132 (2010)). Both FISH and CGH, however, are labor-intensive and time-consuming and require specialized equipment and high-quality tissue samples. Their utility in a clinical setting is accordingly limited. Immunostaining involves the binding of a labeled antibody to a specific protein epitope within a tissue sample, yielding information about protein expression levels or localization. Stains for HMB45, a cytoplasmic premelanosomal glycoprotein, or Ki67, a protein associated with cellular proliferation and ribosomal RNA transcription, are occasionally used in the diagnosis of melanocytic proliferations, although neither stain is absolutely specific nor especially sensitive (Ohsie et al., J. Cutan. Pathol., 35(5): 433-444 (2008)).
Current methods for detection, diagnosis, prognosis, and treatment of melanoma fail to satisfactorily reduce the morbidity and mortality associated with the disease. There is thus a need in the art for additional diagnostic techniques to use in conjunction with traditional histology, particularly diagnostic techniques that are fast, cost-effective, and easy to interpret.